The objectives of this project are 1) to evaluate the neuroendocrine responses to surgical stress and inflammation, 2) to determine the analgesic and anti-inflammatory effects of prototype and novel drugs which alter either the synthesis or the receptor activation of neuroendocrine mediators, and 3) to evaluate the clinical utility of these novel drugs in controlled clinical trials. Previous work on the physiologic function of plasma beta-endorphin and regulation of its release has provided evidence of enhanced release by the nonsteroidal anti-inflammatory drug ibuprofen during surgical stress. A current study is attempting to replicate and extend these findings to postoperative pain. Subjects who have undergone oral surgery remain at the clinic until the onset of moderate to severe pain and are then administered either S(+)-ibuprofen, racemic ibuprofen, or placebo. Blood samples are collected for four hours following drug adminstration for the measurement of the isomers of ibuprofen and beta-endorphin. The S(+) isomer of ibuprofen is the active form of the drug and has been demonstrated to result in higher blood levels than administration of the racemic mixture which requires hepatic conversion of the R(-) isomer to the S(+) isomer and is associated with a delay in onset. Analysis of data from 175 completed subjects indicates that the S(+) isomer results in a faster onset of analgesic activity and greater peak analgesia than the racemic mixture. Laboratory analyses are continuing to determine if a relationship exists between the blood levels of the S(+) isomer, plasma levels of beta-endorphin, and pain relief. A parallel clinical study is attempting to measure inflammatory mediators released following surgery in order to determine the relationship between local levels of inflammatory mediators, clinical reports of pain, and their modulation by ocal infusion of prototypic drugs into the site of inflammation. Subjects undergoing the removal of an impacted third molar have a microdialysis fiber placed under the mucoperiosteal flap which is then slowly perfused to allow diffusion of mediators from the extracellular fluid into the perfusion fluid and administration of drugs from the perfusion fluid into the extracellular space. Technical difficulties in the placement of the probes have resulted in an insufficient patient sample to date to permit conlcusions.